Gut: first published as 10.1136/gut.25.5.513 on 1 May 1984. Downloaded from Gut, 1984, 25, 513-519
Ceruletide increases dose dependently both jejunal motor activity and threshold and tolerance to experimentally induced pain in healthy man
G STACHER, H STEINRINGER, G SCHMIERER, C SCHNEIDER, S WINKLEHNER, G MITTELBACH, C DE PAOLIS, AND C PRAGA From the Psychophysiology Unit at the Psychiatric and First Surgical Clinic, University of Vienna, Vienna, Austria, and Farmitalia Carlo Erba, Milano, Italy
SUMMARY The effects of ceruletide on jejunal motility and experimentally induced pain were studied in 16 healthy men, who participated each in four experiments and received in random double blind fashion 5, 10, or 20 ,g ceruletide intramuscularly or placebo. Jejunal pressures were recorded by three perfused catheters with orifices between 10 and 20 cm aboral of the ligament of Treitz. Ceruletide dose dependently diminished phase I and increased phase II type activity and tended to reduce the number, but not the duration, of activity fronts. The number and amplitude of contractions as well as the area under the curve increased significantly and dose dependently as did threshold and tolerance to electrically and threshold to thermally induced pain. Only mild sedative and other side effects occurred.
Ceruletide (INN proposed by the WHO) or, as it produce a decrement in response to noxious stimula- http://gut.bmj.com/ was named formerly, caerulein is a decapeptide of tion,15 16 in man ceruletide yields prompt and the amino acid sequence Pyr-Gln-Asp-Tyr(SO3H)- complete relief of pain not only from biliary1 19 but Thr-Gly-Trp-Met-Asp-Phe-NH2 and is structurally also from renal colics,17 abolishes cancer pain, 20 and related to the cholecystokinin (CCK) - gastrin alleviates experimentally induced pain.2' 22 The family. It was isolated from the skin of the present study was performed to investigate whether Australian hylid frog Hyla caerulea by the group of synthetic ceruletide (Farmitalia Carlo Erba, Milan, Erspamer' and synthesised subsequently.2 The Italy; purity 94.8%) in doses of 5, 10, and 20 utg peptide has been reported to stimulate myoelectrical intramuscularly would exert both stimulating effects on October 1, 2021 by guest. Protected copyright. spiking as well as the contractile activity of the distal on the motor activity of the upper jejunum and duodenum and the jejunum in man3 4 and, in the analgesic effects on experimentally induced pain in rat,5 to increase the tone of all segments of the small healthy human subjects. intestine except of the duodenum, and to reduce the transit time strikingly not only in healthy subjects Methods but also in patients suffering from postoperative intestinal paralysis.6'l These actions of ceruletide SUBJECTS parallel those of its mammalian counterpart chole- Sixteen healthy men ranging in age from 20 to 32 cystokinin which has been shown to increase dose years (mean 25-4 years) were studied. Only subjects relatedly the motor activity of the jejunum 11-13 and not taking drugs at the time of the experiment, to increase jejunal but not duodenal and ileal spike having regular bowel movements, and without any activity. 14 It has been discovered recently that these history of gastrointestinal disease or previous peptides not only have potent effects on the gastro- abdominal surgery were included. They were given intestinal tract but also are endowed with analgesic a short explanation of the purpose of the research properties: in mice ceruletide and cholecystokinin and a description of the procedures to be followed. They were further given a description of any Address for correspondence: Dr G Stacher, Psychophysiologisches Labora- torium. Psychiatrische Universitatsklinik. Wahringer Gurtel 74-76. A-1090 reasonably foreseeable risks or discomforts. Written Wien, Austria. consent to participate was obtained from each Received for publication 12 August 1983 subject. Before it was initiated, the investigation 513 514 Stacher, Steinringer, Schmierer, Schneider, Winklehner, Mittelbach, De Paolis, and Praga Gut: first published as 10.1136/gut.25.5.513 on 1 May 1984. Downloaded from was approved by the Institutional Committee on on-line at 30 hertz (Hz) by means of a Hewlett- Studies Involving Human Subjects. Packard 21MX E-series computer (Hewlett-Packard Company, Palo Alto, Ca). Jejunal pressures were EXPERIMENTAL DESIGN analysed by a computer program which determined Each subject participated in four experimental for each one minute period the mean end-expiratory sessions at one week intervals. The subjects were base line pressure, the number, the amplitude, and instructed to refrain from eating after 2200 hours on the duration of contractions, as well as the area the evening preceding the experiment, and to eat enclosed by the pressure curve and the base line and drink nothing before coming to the laboratory pressure as an overall index of motility. The pattern on the experimental day. A multilumen polyvinyl of jejunal motor activity was analysed blindly by two tube with recording orifices 3 cm apart and an empty independent observers being unaware of the rubber bag attached to its tip was inserted via the treatment given. The identification of an activity nose into the stomach. The bag was then filled with front or phase III of the fasting pattern of the 2 ml of mercury to facilitate transit. The tube was migrating motor complex (MMC;21 21) was based on positioned under fluoroscopic control so that the three criteria: the appearance of an uninterrupted pressure recording orifices were located between 10 burst of pressure waves of at least three minutes and 20 cm aboral of the ligament of Treitz. After duration and produced at the slow wave frequency this procedure, the subjects reclined on a bed in a of the upper jejunum, the aboral progression of the semirecumbent supine position and remained thus front over all three recording orifices, and a period until the end of the experiment. Ten minutes after of complete quiescence following the activity front. reclining the recording started. Each experiment The recordings of motility in the remaining time comprised 10 15 minute periods. The procedure were divided into phase I, complete quiescence of at during these periods was identical: from minute 1 to least three minutes duration subsequent to an 5, threshold and tolerance to electrically induced activity front and recorded at all three catheter pain, threshold to thermally induced pain, reaction orifices, and phase II, intermittent activity. time to acoustic stimuli, and blood pressure were measured and the subjects asked to complete RespiratDry rate, heart rate, and bloodpressure self-rating scales. During minute 6 to 15, the Respiratory rate was monitored by means of a subjects were instructed to refrain from speaking Beckman strain gauge pneumograph fitted around and from all unnecessary movements. At the the subject's abdomen and a Beckman 9853A http://gut.bmj.com/ beginning of the third 15 minute period, the subjects coupler, and heart rate was processed by a Beckman received, under double blind conditions, intra- 9857 cardiotachometer coupler on the base of a muscular injections of either (1) 5 ug ceruletide, (2) chest wall electrocardiogram. Systolic and diastolic 10 ,ug ceruletide, (3) 20 ,ug ceruletide or (4) saline blood pressure were recorded by means of an placebo (0.15 M). The sequence in which they automatic device (Boso-Digimat, Bosch & Sohn, received the treatments on the different days was Jungingen, West Germany) and an inflatable cuff randomised according to a plan with four 4x4 Latin around the non-dominant arm. squares. on October 1, 2021 by guest. Protected copyright. Threshold and tolerance to electrically induced pain Measurement of jejunal motor activity Chains of square wave constant current impulses of Jejunal pressures were recorded continuously by 1 millisecond duration and a pulse frequency of 30 means of a multilumen catheter assembly and three Hz were used to induce pain.25-27 The intensity of orifices spaced at 3 cm intervals (Mui Scientific, the impulses increased, in steps of 0-05 milliampere, Mississauga, Ontario, Canada). The catheters were linearly from zero to 12-8 milliampere, the maxi- perfused with distilled water by means of a mum intensity being reached within 25-6 seconds. pressurised capillary hydraulic infusion system (Mui The stimuli were administered by means of a pair of Scientific) at 70 kilopascal (525 millimetres of silver ball electrodes attached to the earlobe of the mercury (mmHg)). Pressures were transmitted to subjects' non-dominant side. The subjects were Beckman Type 4-327C transducers (Beckman given a handle fitted with two push buttons and Instruments, Inc, Schiller Park, Ill). The compliance instructed to press the left button as soon as they of the entire recording system was such that a perceived the stimuli as painful and thereby to sudden occlusion of the perfused catheters produced indicate pain threshold, and to press the right button a pressure rise of at least 100 mmHg per second. The when they felt they could not tolerate any further output of the transducers was recorded on a increase of stimulus intensity and thereby to indicate Beckman R-411 Dynograph using Beckman 9853A pain tolerance. Pressing the second button stopped couplers. The amplified signals then were digitised the stimulation. Six chains of stimuli were pre- Jejunal and analgesic effects of ceruletide 515 Gut: first published as 10.1136/gut.25.5.513 on 1 May 1984. Downloaded from sented. The interval between the chains ranged the fixed within subjects factors 'treatment' (one to randomly from 15 to 25 seconds. four), 'day' (experimental days one to four), 'time' (periods 1-30, 31-60, 61-90, and 91-120 minutes Threshold to thermally induced pain after drug administration), as well as of the random Radiant heat of a constant intensity was used to factor 'subject' (one to 16). On the basis of the induce pain.27 28 On the volar surface of the analysis of variance, linear and quadratic contrasts subjects' dominant forearm, six spots were marked over the mean effects of the three doses of and numbered from one to six. The subjects were ceruletide were calculated to investigate dose required to press these spots sequentially against a response relationships, and a sequentially rejective switch mounted at an aperture, 6x6 mm in size, on multiple test procedure30 was used to evaluate the stimulator. Without prior notice a projection differences between the treatment effects. In the filament lamp mounted within the stimulator was latter procedure, an overall significance level of then turned on. The subjects were instructed to pull a=0 05 was adopted. their forearm away from the aperture as soon as they perceived the radiant heat stimulus as painful Results and thereby to indicate their pain threshold. The time elapsing between the turning on of the lamp The analyses revealed that the factor 'day', that is and the withdrawal of the arm, allowing the closure the sequence in which the subjects received the four of the switch, was measured by a digital clock. The treatments in the different sessions, had no signifi- intervals between the applications of the stimuli cant influence on their responses in any one ranged randomly from 15 to 25 seconds. measure.
Reaction time to acoustic stimuli JEJUNAL MOTOR ACTIVITY Reaction time to acoustic stimuli was recorded in 1 Pattern of motor activity response to six tones presented with random After the administration of ceruletide, the intervals ranging from 10 to 20 seconds. percentage of motility recordings classified as phase I of the fasting pattern of the MMC decreased, Self-rating scales whereas the percentage of tracings classified as Visual analogue scales containing 14 pairs of polar phase II increased dose dependently The (Table 1). http://gut.bmj.com/ adjectives, written on the right and the left edge of a analysis showed that the treatment effects differed sheet of paper, were used. Between the two words significantly (phase I: F(3,168)=4.02, p<0-01; phase there was a 10 cm line and the subjects were II: F(3,168)=5-64, p<0002), and that there were instructed to mark that point of the line, which they significant linear dose response relationships (phase considered to indicate most correctly their feelings I: F(1,168)=9.43, p<0O005; phase II: in the given moment. Each three pairs of adjectives F(1,168)= 14*77, p<0001). Twenty micrograms were aimed to obtain information on activation ceruletide produced significantly larger shifts in ('awake - drowsy', 'quick - slow', 'enterprising - phases I and II than did placebo and 5 ,ug of the on October 1, 2021 by guest. Protected copyright. inert') and on wellbeing ('happy - unhappy', peptide. A total of 72 activity fronts (phase III) were 'pleasant - unpleasant', 'oppressed - free'), while observed in the 64 experimental sessions. Of these one pair ('warm - cold') was aimed to quantify fronts, 27 occurred in the basal 30 and 45 minutes feelings of warmth. The remaining pairs were after drug administration. The number of activity non-relevant to the above dimensions. The mean fronts, but not their duration, tended to diminish ratings in each dimension were analysed. with increasing dose of ceruletide (correlation coefficient, r=0-904, p<01): 14 fronts with a mean Side effects duration of 7.4 min±09 SEM were recorded after Side effects as reported spontaneously by the subjects were recorded together with the experimenters' observations. Table 1 Percent distribution (mean ± SEM) ofphases I, II, and III ofthefasting pattern ofthe migrating motor STATISTICAL ANALYSIS OF DATA complex in the 120 min after drug administration An analysis of variance for repeated measures29 was Phase I Phase 11 Phase III performed on the differences between the mean values of each two consecutive 15 minute periods Placebo 18-8±4-7 76-1±4-8 5-1±1-0 after drug administration (1-30, 31-60, 61-90, 91- 5 ug ceruletide 19-2±3-0 75 6±3 5 5-2±0 8 120 minutes) and the mean values of the two basal 10 ,Ag ceruletide 14-0±3-4 81-2±4-3 4-8±1-2 periods. The analysis investigated the influences of 20Agceruletide 4 8±1-9 92-1±2-6 3 1±1-0 516 Stacher, Steinringer, Schmierer, Schneider, Winklehner, Mittelbach, De Paolis, and Praga Gut: first published as 10.1136/gut.25.5.513 on 1 May 1984. Downloaded from the administration of 5 ug ceruletide, 10 fronts with increased markedly and in a dose related manner by a mean duration of 7-8±1-2 minutes after 10 Ag, and ceruletide, while it was not altered by placebo eight fronts with a mean duration of 9-1±1-4 (Table 2). The analysis revealed significantly minutes after 20 ,ug of the peptide, as compared with diffe-ring treatment effects (F(3, 168)=9-23, 13 activity fronts lasting 7-9±0-7 minutes after p<0.001) and a linear dose response relationship placebo. (F(1,168)=17-68, p<0.001). Ten and 20 ,tg ceruletide were significantly more active than 2 Number of contractions placebo, and 20 ,ug ceruletide more than 5 and 10 ,ug The number of jejunal contractions irrespective of of the peptide. the phases of the MMC increased dose dependently after administration of ceruletide, while it remained Heart rate, blood pressure, and respiratory rate unchanged after placebo. With the two lower doses Heart rate, blood pressure, and respiratory rate of ceruletide, the effects lasted for about 60 and 90 were not altered systematically by any of the three minutes, respectively, whereas with 20 ,g ceruletide doses of ceruletide. the number of contractions was still raised 120 minutes after administration (Table 2). The analysis THRESHOLD TO ELECTRICALLY INDUCED PAIN revealed significantly differing treatment effects Threshold increased after the administration of all (F(3,168)=8-09, p<0.001) and a significant linear doses of ceruletide, 5 and 10 ,g being about equally dose response relationship (F(1,168)= 18-26, effective and 20 ,ug having the strongest effect. p<0.001). Twenty micrograms ceruletide produced Maximal effects were reached between 30 and 60 significantly more contractions than each of the minutes, thereafter threshold levels remained high other treatments. until the end of the experimental time. With placebo, only slight rises of threshold occurred 3 Mean amplitude of contractions (Table 3). The treatment effects differed signifi- The mean amplitude increased dose dependently cantly (F(3,168)=11 25, p<0-001), and all doses of after ceruletide, whereas it decreased slightly after ceruletide were significantly more active than placebo. The effects of 5 and 10 ,ug ceruletide lasted placebo. Twenty jig ceruletide were significantly up to 90 minutes, while 20 ug were still active after superior in analgesic efficacy to 5 and 10 ,ug, 120 minutes (Table 2). The treatment means whereas the actions of the latter two doses did not differed significantly (F(3,168)= 13-36, p<0.001) differ from each other. The investigation of dose http://gut.bmj.com/ and there was a significant linear dose response response relationships revealed significant F ratios relationship (F(1,168)=15-42, p<0001). The effects for a linear (F(1,168)=12.04, p<0-001) but also for of all doses of ceruletide differed significantly from a quadratic relationship (F(1,168)=4-07, p<0.05), placebo and 20 ug of the peptide were significantly reflecting the fact that the effects of the two lower more active than 5 and 10 ,ug, respectively. ceruletide doses did not differ.
4 Area under the curve TOLERANCE TO ELECTRICALLY INDUCED PAIN on October 1, 2021 by guest. Protected copyright. This measure of overall contractile activity was All doses of ceruletide caused marked increases of
Table 2 Number ofjejunal contractions per minute, mean amplitude ofcontractionis. and area under the curve (mean ± SEM) in the 30 minutes before (period 1) and in the four 30 minute periods after dru(g administration1 (periods 2 to 5) Period Treatment 1 2 3 4 5 Numberof contractions Placebo 2 8+0 2 2 7(±03 2'7±0(3 ' 9+0 3 27+±0)3 perminute SAgceruletide 2 8+0 2 3 3±0+3 ' 9+0' 27±0 3 24+40)2 10l0gceruletide 2-6+±03 3-1+±0' 3-0±0(3 2'5+0 3 '24+0-3 20 Ag ceruletide 23+±0)3 3 1±0' 3 5+±0(3 2'9+0 3 2'7+0 2 Mean amplitude (mmHg) Placebo 85±0 7 7 1±1 0 6 9±0 8 7 7±0 8 7 1±0 8 5Mgceruletide 8 ()008 9 4±1 0 8 1±0+7 7 5±0 8 6 9±0+7 10 Agceruletide 7 7±0+6 9 1±0+7 8 8±0+6 7 3±0 8 7 1±0+7 20,ug ceruletide 7'2+0 8 95±1 1 10(3±0+9 8 9±0 8 7 6±0 5 Area under the curve Placebo 6506±719 5915±1009 5754± 1031 6783±1045 5793±986 5 ,g ceruletide 7370±994 9250± 1248 7744± 1019 6794±957 5897±900 10lOg ceruletide 6144±822 8985 ±1059 82'41 ± 1007 6524±1170 6075 ± 1 163 20 gg ceruletide 5708±792 9539± 1539 11159± 1666 8524± 1235 6748+8(X) Jejulnal anid analgesic effects of ceruletide 517 Gut: first published as 10.1136/gut.25.5.513 on 1 May 1984. Downloaded from
Table 3 Threshold and tolerance to electrically induced pain and threshold to thermally induced pain (means ± SEM) in the 30 minutes before (period 1) and in thefour 30 minute periods after drug administration (periods 2 to 5)
Period Treatment 1 2 3 4 5 Threshold to electrically Placebo 1 08+0 17 1-08+±019 1-28+±026 1-32+0-27 1-36+0-28 induced pain (milliampere) 5 ,g ceruletide 1 07+0 16 1 43+027 1 45+±0(28 1-45+±0)26 1 43±0 24 10(,g ceruletide 107+0 14 1 36+±017 144+0()20 1 47+±018 1 48+±019 20,.g ceruletide 1 16+0-20 1 57+(0)-9 1-83+±037 i 89±0+41 1 90±0 38 Tolerance to electrically Placebo 1 96+±025 1 94+±032 2 23+±040 2 31 +±031 2 29+0 32 induced pain (milliampere) 5 ,ug ceruletide 1 81 +019 2 23+0 31 2-28+±032 2 27+±0)30 2 27+0 29 10 Ag ceruletide 1 75+±019 2 14+0 25 2 19+±028 2 23+±027 2-22±0 27 20 ,tg ceruletide 1 99+±028 2 64±0(43 2 86+±048 2 90±+050 2 96±0 49 Threshold to thermally Placebo 1841+44 1844±43 1852+43 1881±42 1879+40 induced pain (milliseconds) 5 Aug ceruletide 1786+36 1877+37 1891+39 1925+30 1914+39 10 jig ceruletide 1742+31) 1815±29 1871±34 1898±31 1906+34 20 ,Ag ceruletide 1727+45 1835+44 1877±41 1881+44 1876+49 pain tolerance, 20 ,ug being most effective, while the ceruletide, the maximum effect being reached effects of 5 and 10 gg were weaker and nearly between 60 and 90 minutes after administration. identical. Placebo caused only slight changes (Table The treatment effects differed significantly 3). The treatment effects differed significantly (F(3.168)=8.66. p 518 Stacher, Steinringer, Schmierer, Schneider, Winklehner, Mittelbach, De Paolis, and Praga tions and also increased the area under pressure with results from clinical studies,610 seem to curve - that is, overall motor activity. Thus, indicate the need for a further investigation of the ceruletide elicited a contractile pattern which potentially beneficial effects of ceruletide in the resembled postprandial activity. These findings are postoperative phase, where intestinal atonia as well in accordance with results from animal studies, in as pain pose serious therapeutic problems. which similar results were found with both ceruletide7 31 and cholecystokinin.24 32 There is no unanimity as to the functional significance of the motility pattern induced by these peptides. It seems, however, that both mixing and propulsion of small References intestinal contents are enhanced,6 31 as the main part of propulsion occurs during phase II.33 The 1 Anastasi A, Erspamer V, Endean R. Isolation and doses in which ceruletide acts on the jejunum are amino acid sequence of caerulein, the active decapep- about in the same range as the doses of ceruletide tide of the skin of Hyla caerulea. Arch Biochem 1968; of 125: 57-68. and cholecystokinin eliciting cholecystokinetic 2 Bernardi L, Bosisio G, de Castiglione R, Goffredo 0. and pancreozyminic actions and inhibiting gastric Synthesis of caerulein. Experientia 1967; 23: 700-1. emptying, all of which are considered to be physio- 3 Bertaccini G, Agosti A. Action of caerulein on logical actions of cholecystokinin.34 3 intestinal motility in man. Gastroenterology 1971; 60: Ceruletide also produced dose dependent effects 55-63. on threshold and tolerance to electrically induced 4 Lab6 G, Barbara L, Lanfranchi GA, Bortolotti M, pain and on threshold to thermally induced pain. Miglioli M. Modification of the electrical activity of the These actions lasted longer - that is, until the end of human intestine after serotonin and caerulein. Am J the 120 minute period after drug administration, Dig Dis 1972; 17: 363-72. than the effects on the jejunum. The 5 Scott LD, Summers RW. Effect of glucagon and http://gut.bmj.com/ analgesia caerulein on propulsion and motility in the rat small produced by 5 and 10 Ag ceruletide was of similar intestine. Gastroenterology 1974; 66: 774. magnitude to that produced by intravenous doses of 6 Bertaccini G. Action of caerulein on gastrointestinal 4.2 and 8&4 Ag/h/70 kg body weight in an earlier motility in healthy subjects and patients: in vivo and in investigation 1 2. Twenty micrograms ceruletide vitro studies. Rendic Rom Gastroenterol 1971; 3: 122. was significantly superior in analgesic efficacy to 7 Agosti A, Bertaccini G, Paulucci R, Zanella E. both 5 and 10 ,ug of the peptide and yielded effects Caerulein treatment for paralytic ileus. Lancet 1971; 1: 395. comparable with those produced by 28 mg/h/70 kg on October 1, 2021 by guest. Protected copyright. body weight pentazocine intravenously in the above 8 Haas W, Rueff FL. Caerulein in der Therapie der mentioned study.22 In parallel to earlier investi- postoperativen Darmatonie und des Ileus. 21 Therapiewoche 1978; 28: 8939-44. gations, 22 36 ceruletide caused only mild sedative 9 Montero VF, Laganga AM, Garcia EA. Usefulness of and other side effects. With all doses of the peptide, caerulein in the treatment of post-operative intestinal however, the subjects reported less well being on atony. J Int Med Res 1980; 8: 98-104. self rating scales than with placebo. The mechanism 10 Madsen PV, Lykkegaard-Nielsen M, Nielsen OV. by which ceruletide produces analgesia remains to Ceruletide reduces post-operative intestinal paralysis. be clarified. A direct central effect seems unlikely, A double-blind placebo-controlled trial. Dis Colon as peripherally administered ceruletide or chole- Rectum 1983; 26: 159-60. cystokinin do not readily pass the blood brain 11 Gutierrez JG, Chey WY, Dinoso VP. Actions of barrier.37-40 The fact that is present cholecystokinin and secretin on the motor activity of cholec,ystokinin the small intestine in man. Gastroenterology 1974; 67: in primary sensory neurones, in vagal afferent 35-41. fibres,42 and in splanchnic and somatic peripheral 12 Dollinger HC, Berz R, Raptis S, Uexkull T von, nerves42 43 suggests that it acts as an active neuro- Goebell H. Effects of secretin and cholecystokinin on transmitter in these locations and thus may play a motor activity of human jejunum. Digestion 1975; 12: role in the processing of sensory and nociceptive 9-16. information. 13 Fleckenstein P, Oigaard A. Effects of cholecystokinin It is concluded that ceruletide, in healthy man, on the motility of the distal duodenum and the stimulates fasting jejunal motor activity and proximal jejunum in man. Scand J Gastroenterol 1977; increases threshold and tolerance to experimentally 12: 375-8. 14 Wingate DL, Pearce EA, Hutton M, Dand A, induced pain significantly and in a dose dependent Thompson HH, Wunsch E. Quantitative comparison fashion. Although it can not be assumed that the of the effects of cholecystokinin, secretin, and penta- same stimulatory effects on jejunal motor activity gastrin on gastrointestinal myoelectric activity in the will occur also in patients suffering from post- conscious fasted dog. Gut 1978; 19: 593-601. operative hypomotility, the present results, together 15 Jurna I, Zetler G. Analgesia following central adminis- Jejunal and analgesic effects of ceruletide 519 Gut: first published as 10.1136/gut.25.5.513 on 1 May 1984. Downloaded from tration of caerulein and cholecystokinin octapeptide 29 Games PA. Computer programs for robust analyses in (CCK-8). Naunyn Schmiedebergs Arch Pharmacol multifactor analysis of variance designs. Educ Psychol 1980; 13 (suppl): R26. Measure 1975; 35: 147-52. 16 Zetler G. Analgesia and ptosis caused by caerulein and 30 Holme S. A simple sequentially rejective multiple test cholecystokinin octapeptide (CCK-8). Neuropharma- procedure. Scand J Stat 1979; 6: 65-70. cology 1980; 19: 415-22. 31 Scott LD, Summers RW. Correlation of contractions 17 Basso N, Bagarani M, Gizzonio D et al. Analgesic and transit in rat small intestine. Am J Physiol 1976; effect of ceruletide (CRL) in biliary and renal colic. 230: 132-7. Gastroenterology 1981; 80: 1105. 32 Mukhopadhyay AK, Thor PJ, Copeland EM, Johnson 18 Basso N, Materia A, Fiocca M et al. Treatment of LR, Weisbrodt NW. Effect of cholecystokinin on biliary colic with ceruletide. Gastroenterology 1980; 78: myoelectric activity of small bowel of the dog. Am J 1137. Phvsiol 1977; 232: E44-7. 19 Santamaria A, Lucani G, Montorsi M, Praga C. Action 33 Bueno L, Fioramonti J, Ruckebusch Y. Rate of flow of de la ceruleine sur la colique hepatique. Nouv Presse digesta and electrical activity of the small intestine in Med 1979; 8: 2482. dogs and sheep. J Physiol (Lond) 1975; 249: 69-85. 20 Piazza E, Brambilla M, Cattaneo MT, Martini A, 34 Debas HT, Farooq 0, Grossman MI. Inhibition of Pacciarini MA. Analgesic activity of ceruletide in gastric emptying is a physiological action of cholecysto- cancer patients. In: Basso N, Lezoche E, Speranza V, kinin. Gastroenterology 1975; 68: 1211-7. Walsh JH, eds. International symposium on brain-gut 35 Valenzuela JE, Grossman MI. Effect of pentagastrin axis: the new frontier, Florence, June 29/30 - July 1, and caerulein on intragastric pressure in the dog. 1981 [Abstracts]. Florence, 1981: 146. Gastroenterology 1975; 69: 1383-4. 21 Stacher G, Schmierer G, Steinringer H, Schneider C, 36 Stacher G, Steinringer G, Schmierer G, Schneider C, Winklehner S. Ceruletide alleviates experimentally Winklehner S. Ceruletide decreases food intake in induced pain. Regul Pept 1983; suppl 2: S109. non-obese man. Peptides 1982; 3: 607-12. 22 Stacher G, Steinringer H, Schmierer G, Winklehner S, 37 Cornford EM, Braun LD, Crane PD, Oldendorf WH. Schneider C. Ceruletide increases threshold and Blood-brain barrier restriction of peptides and the tolerance to experimentally induced pain in healthy lower uptake of enkephalin. Endocrinology 1978; 103: man. Peptides 1982; 3: 955-62. 1297-303. 23 Code CF, Marlett JA. The interdigestive myo-electric 38 Kruse-Larsen C, Rehfeld JF. Gastrin in human complex of the stomach and small bowel of dogs. cerebrospinal fluid: lack of correlation with serum J Physiol (Lond) 1975; 246: 289-309. concentrations. Brain Res 1979; 176: 189-91. 24 Vantrappen G, Janssens J, Hellemans J, Ghoos Y. The 39 Debas H, Yamada T, Oldendorf W, Passaro E Jr. The interdigestive motor complex of normal subjects and permeability of blood-brain and brain-blood barrier to http://gut.bmj.com/ patients with bacterial overgrowth of the small the octapeptide of CCK. In: Basso N, Lezoche E, intestine. J Clin Invest 1977; 59: 1158-66. Speranza V, Walsh JH, eds. International symposium 25 Lahoda R, Stacher G, Bauer P. Experimentally on brain-gut axis: the new frontier, Florence, June 29/30 induced pain: measurement of pain threshold and pain - July 1, 1981 [Abstracts]. Florence, 1981: 47. tolerance using a new apparatus for electrical stimula- 40 Zhu XG, Lewis BG, Lilja P, Greely G, Thompson JC. tion of the skin. Int J Clin Pharmacol 1977; 15: 51-6. Effects of cholecystokinin and bombesin on concentra- 26 Stacher G, Bauer P, Ehn I, Schreiber E. Effects of tions of cholecystokinin in plasma and cerebral spinal tolmetin, paracetamol, and of two combinations of fluid in dogs. Gastroenterology 1982; 82: 1218. on October 1, 2021 by guest. Protected copyright. tolmetin and paracetamol as compared to placebo on 41 Larsson LI, Rehfeld JF. Localization and molecular experimentally induced pain. A double blind study. Int heterogeneity of cholecystokinin in the central and J Clin Pharmacol 1979; 17: 250-5 peripheral nervous system. Brain Res 1979; 165: 27 Stacher G, Bauer P, Schneider C, Winklehner S, 201-18. Schmierer G. Effects of a combination of naproxen 42 Dockray GJ, Gregory RA, Tracy HJ, Zhu WY. sodium and codein per os on experimentally induced Transport of cholecystokinin-octapeptide-like immuno- pain. Eur J Clin Pharmacol 1982; 21: 485-90. reactivity toward the gut in afferent vagal fibers in cat 28 Wohlzogen FX, Weish P. Vergleichende Analgetika- and dog. J Physiol (Lond) 1981; 314: 501-11. prufung unter Verwendung der Schmerzschwellenzeit 43 Rehfeld JF, Larsson LI, Goltermann NR et al. Neural bei thermischer Hautreizung als Kriterium fur die regulation of pancreatic hormone secretion by the analgetische Wirkung. Wien Klin Wochenschr 1969; 81: C-terminal tetrapeptide of CCK. Nature 1980; 284: 616-8. 33-8.